Global Approaches to Elucidate the Function of Post-transcriptional Networks in HIV-1 Infection

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Human immunodeficiency virus type 1 (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), which constitutes one of the most important pandemics of our time. From the 60 million people that have been infected with HIV-1, 25 million have dead. Very important advances have been done to better understand HIV-1 infection in the past. However, the technical developments achieved in the last decade open now the possibility of exploring an infected cell in an unprecedented depth. Once HIV-1 penetrated into the host cell the viral particles disassemble, releasing the genomic RNA that is covered by viral and host proteins. This protein-RNA complex travels towards the nucleus and, during the path, HIV-1 genomic RNA is reverse transcribed into DNA to form the provirus. Once in the nucleus, the provirus is integrated into the cellular chromosome. Synthesis, processing and transport back to the cytoplasm of newly synthesized HIV-1 RNAs are mediated by the host machinery. Importantly, translation of HIV-1 RNAs is exerted by cellular protein synthesis machinery, producing the viral proteins required to generate the viral progeny. Therefore, HIV-1 relies on cellular resources from the entrance in the infected cell to the release of viral progeny. Because HIV-1 strongly relies on host gene expression machinery, scientists envision that inhibition of a cellular function that is required for viral replication and does not compromise cell survival, will represent an alternative strategy to treat HIV-1 infection.RNA-binding proteins are key "players" of gene expression machinery and this protein class has emerged as crucial regulators of HIV-1 infection. However, to identify novel therapeutic targets, scientists have first to determine the exact repertoire of cellular proteins involved in HIV-1 replication. To date this catalog of host factors is still incomplete in spite of the numerous efforts undertaken to better understand HIV-1-host cell interactions. The methods that I developed during my postdoctoral work offer now the possibility to globally define the scope of host proteins that directly interact with HIV-1 genomic RNA. The repertoire of proteins identified by these methods will be studied in detail in cultured cells and mouse models using different biochemical approaches. Proteins proven by these analyses to play an essential role in HIV-1 replication may represent potential host-based targets to treat the infection. Therefore, this project aims at finding potential therapeutic targets by expanding our knowledge in HIV-1 biology using novel system-wide approaches.